title: Soluble GARP has potent antiinflammatory and immunomodulatory impact on human CD4⁺ T cells.
abstract: Glycoprotein A repetitions predominant (GARP) is expressed on the surface of activated human regulatory T cells (Treg) and regulates the bioavailability of transforming growth factor-β (TGF-β). GARP has been assumed to require membrane anchoring. To investigate the function of GARP in more detail, we generated a soluble GARP protein (sGARP) and analyzed its impact on differentiation and activation of human CD4⁺ T cells. We demonstrate that sGARP efficiently represses proliferation and differentiation of naïve CD4⁺ T cells into T effector cells. Exposure to sGARP induces Foxp3, decreases proliferation and represses interleukin (IL)-2 and interferon-γ production, resulting in differentiation of naïve T cells into induced Treg. This is associated with Smad2/3 phosphorylation and partially inhibited by blockade of TGF-β signaling. Furthermore, in the presence of the proinflammatory cytokines IL-6 and IL-23, sGARP facilitates the differentiation of naïve T cells into Th17 cells. More important, in a preclinical humanized mouse model of xenogeneic graft-versus-host disease (GVHD), sGARP prevents T cell-mediated destructive inflammation by enhancing Treg and inhibiting T effector cell activity. These results demonstrate a crucial role of sGARP in modulation of peripheral tolerance and T effector cell function, opening the possibility to use sGARP as a potent immunomodulator of inflammatory diseases including transplant rejection, autoimmunity, and allergy.
authors.affiliation: Department of Dermatology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Susanne A
authors.initials: SA
authors.lastname: Hahn
authors.forename: Heiko F
authors.initials: HF
authors.lastname: Stahl
authors.forename: Christian
authors.initials: C
authors.lastname: Becker
authors.forename: Anita
authors.initials: A
authors.lastname: Correll
authors.forename: Franz-Joseph
authors.initials: FJ
authors.lastname: Schneider
authors.forename: Andrea
authors.initials: A
authors.lastname: Tuettenberg
authors.forename: Helmut
authors.initials: H
authors.lastname: Jonuleit
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006086:Graft vs Host Disease / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D000893:Anti-Inflammatory Agents; D004268:DNA-Binding Proteins; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007376:Interleukin-2; D007378:Interleukins; C087215:LRRC32 protein, human; D008565:Membrane Proteins; D012333:RNA, Messenger; C499308:Rag2 protein, mouse; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma